CN115427022A - Pharmaceutical composition, preparation method and use method thereof - Google Patents

Pharmaceutical composition, preparation method and use method thereof Download PDF

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CN115427022A
CN115427022A CN202180022930.5A CN202180022930A CN115427022A CN 115427022 A CN115427022 A CN 115427022A CN 202180022930 A CN202180022930 A CN 202180022930A CN 115427022 A CN115427022 A CN 115427022A
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pharmaceutical composition
hot melt
melt extrusion
pharmaceutically acceptable
parts
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CN115427022B (en
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吴劲梓
柴旭煜
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Ganglai Pharmaceutical Co ltd
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Ganglai Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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    • A—HUMAN NECESSITIES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Abstract

The present invention describes pharmaceutical compositions suitable for long-term storage at room temperature. The pharmaceutical compositions comprise compounds of formula (I) and are useful for treating steatohepatitis. Methods for preparing the pharmaceutical compositions and methods of treatment using the pharmaceutical compositions are also described.

Description

Pharmaceutical composition, preparation method and use method thereof
RELATED APPLICATIONS
The present application claims priority to chinese application number 2020102271770 filed on 27/3/2020. The entire contents of the above-mentioned application are incorporated by reference into the present application.
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a cyclic phosphonate pharmaceutical composition suitable for room-temperature storage and a preparation method thereof.
Background
The storage conditions of the drug product are a reflection of the stability of the drug in the drug product. Lower melting drugs or crystalline forms are generally relatively less stable and require storage at lower temperatures, while higher melting drugs or crystalline forms have better stability and can generally be stored at room temperature. The reasonable processing temperature of the preparation should also be reasonably established according to the thermal stability of the drug. Thermal degradation of drugs is often closely related to their melting point, and after 20 ℃ above this melting point, the degradation reaction occurs rapidly.
Steatohepatitis is a chronic inflammatory disease, and long-term administration is preferred. The requirement for low temperature storage adds a great deal of inconvenience to the patient's long-term administration and may result in missed or improper storage, which may affect the therapeutic effect and may lead to delayed or repeated episodes of the disease. In addition, the low-temperature refrigeration condition is equipped with a special cold chain transport vehicle and a long-term refrigerator, which brings additional cost to the commercial development of the product.
Therefore, in order to better satisfy clinical and commercial requirements, it is necessary to find a stable pharmaceutical formulation and a preparation method that can be stored at room temperature. Such a formulation would not only greatly increase the in vivo and in vitro dissolution of the active ingredient, but, more importantly, enable storage at room temperature.
The compound of formula (I) (formula C28H32ClO5P, molecular weight 514.98, cas registry number 852948-13-1) is a novel oral thyroid hormone beta receptor (THR-beta) agonist that effectively promotes fatty acid breakdown and stimulates mitochondrial biogenesis by selectively activating THR-beta and regulating expression of downstream genes such as CYP7A and SREBP-1C, reduces low density lipoprotein and triglyceride levels, thereby reducing lipotoxicity and improving liver function and reducing liver fat, and is therefore a candidate for highly potent and low-toxic non-alcoholic steatohepatitis.
Figure BDA0003851854170000021
The compound shown in the formula (I) is a strong fat-soluble (lipophilic) insoluble drug, and the solubility of the compound in hydrochloric acid solution, buffer solution and water at 37 ℃ and pH of 1.0-9.0 without adding a surfactant is lower than 0.5ng/mL. The extremely low solubility limits its use in the development of drug candidates. Chinese patent application 202010105909.9 reports a semi-solid capsule technology that can dramatically increase the dissolution of the compound of formula (I), but the capsule needs to be stored in a cool place below room temperature (no more than 15 ℃), especially in a closed container at 2 ℃ to 8 ℃.
Therefore, there is still a need to develop a formulation which will allow the long term storage of pharmaceutical compositions comprising compounds of formula (I) at room temperature.
Disclosure of Invention
After extensive exploration and comparison of different types and ratios of excipients and process parameters, the inventors have unexpectedly found that a high temperature hot melt extrusion process (above 80 ℃) is suitable for preparing solubilized compositions of formula (I) and that products prepared using the formulations and methods described herein exhibit increased dissolution and long-term stability of formula (I) at room temperature, which is of great importance for improving patient compliance and safety as well as reducing transportation and storage costs.
One aspect of the present application relates to a pharmaceutical composition comprising the following components in parts by weight: (a) 1 part of a compound of formula (la) and (b) 15 to 45 parts of copovidone having a glass transition temperature of 90 to 130 ℃, wherein components (a) and (b) are mixed and subjected to hot melt extrusion.
Another aspect of the present application relates to a pharmaceutical composition comprising the following components in parts by weight: (a) 1 part of a compound of formula (I) and (b) 6 to 20 parts of hydroxypropylmethylcellulose having a glass transition temperature of 90 to 130 ℃, wherein components (a) and (b) are mixed and subjected to hot melt extrusion.
Another aspect of the present application relates to a method of preparing a pharmaceutical composition of the present application.
Another aspect of the present application relates to a method for treating steatohepatitis in a subject. The method comprises the step of administering to the subject an effective amount of a pharmaceutical composition of the present application.
Drawings
Fig. 1 is the dissolution profile in water of a composition prepared according to the A1-F1 formulation in example 1 (effect example 1) (n = 6);
fig. 2 is a dissolution profile in water of a composition prepared according to the a2-d2 formulation in comparative examples 1-3 (effect example 1) (n = 6);
fig. 3 is a dissolution profile (effect example 2) (n = 6) for a composition prepared according to the G1-L1 formulation in example 2;
fig. 4 is a dissolution profile (effect example 2) (n = 6) of a composition prepared according to the e2-g2 formulation in comparative examples 4-5.
While the present disclosure will now be described in detail and with reference to illustrative embodiments thereof, the present disclosure is not limited to the specific embodiments shown in the drawings and the appended claims.
Detailed Description
Reference will now be made in detail to certain aspects and exemplary embodiments of the present application, and to the illustrative embodiments in the accompanying structures and drawings. Various aspects of the present application, including methods, materials, and examples, will be described in conjunction with exemplary embodiments, such description is non-limiting, and the scope of the present application is intended to encompass all equivalents, alternatives, and modifications commonly known or incorporated herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Those skilled in the art will recognize many techniques and materials similar or equivalent to those described herein, which may be used in the practice of the various aspects and embodiments of the present application. The described aspects and embodiments of the present application are not limited to the methods and materials described.
As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise.
Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It will also be understood that a number of values are disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value of "less than or equal to" the value, "greater than or equal to the value" is disclosed, then possible ranges between the values are also disclosed, as is well understood by those skilled in the art. For example, if the value "10" is disclosed, then "less than or equal to 10" and "greater than or equal to 10" are also disclosed.
The term "pharmaceutically acceptable excipient" as used herein refers to one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to humans. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ or portion of the body to another organ or portion of the body. The term "carrier" means an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is associated to facilitate administration. Each adjuvant or carrier must be "acceptable" in the sense of being compatible with the subject composition and components thereof and not injurious to the patient. The components of the pharmaceutical composition can also be mixed together with the molecules of the present invention and with each other in a manner that does not have an interaction that would significantly impair the desired pharmaceutical efficacy.
The term "effective amount" as used herein refers to a therapeutic amount required to alleviate at least one or more symptoms of a disease or disorder (e.g., inflammation or nephritis) and relates to a sufficient amount of the pharmacological composition to provide a desired effect. Thus, the term "therapeutically effective amount" refers to a therapeutic amount sufficient to elicit a particular effect when administered to a typical subject. As used herein, an effective amount, in each case, will also include an amount sufficient to delay the development of symptoms of a disease, alter the progression of symptoms of a disease (such as, but not limited to, slowing the progression of a disease), or reverse the symptoms of a disease. Thus, it is often impractical to specify an exact "effective amount". However, for any given situation, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation.
I. Extruding the mixture
One aspect of the present application relates to an extrusion mixture for hot melt extrusion. The extrusion mixture comprises (a) a compound of formula (I) and
Figure BDA0003851854170000061
(b) The medium is extruded.
In some embodiments, the compound of formula (I) is in a crystalline form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in an amorphous form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in the form of a hydrate or solvate.
Examples of extrusion media include, but are not limited to, copovidone and hydroxypropyl methylcellulose.
In some embodiments, the extrusion mixture further comprises (c) one or more pharmaceutically acceptable excipients.
In the preparation of the pharmaceutical compositions of the present application, the extrusion mixture is extruded by hot melt extrusion to form an extrudate. The extrudate is cooled, comminuted or cut into granules or powders, optionally mixed with one or more pharmaceutically acceptable carriers, and used to prepare the pharmaceutical compositions of the present application. In some embodiments, the pharmaceutical compositions of the present application are used to treat steatohepatitis.
Extrusion mixtures comprising copovidone
In some embodiments, the extrusion mixture comprises the following components in parts by weight:
(a) 1 part of a compound of formula (I) and (b) 5 to 70 parts of copovidone having a glass transition temperature of 90 to 130 ℃.
In some embodiments, the compound of formula (I) is in a crystalline form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in an amorphous form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in the form of a hydrate or solvate.
In some embodiments, the copovidone has a glass transition temperature of 90 ℃ to 120 ℃. In some embodiments, the copovidone has a glass transition temperature of 100 ℃ to 120 ℃. In some embodiments, the copovidone has a glass transition temperature of 90 ℃ to 110 ℃. In some embodiments, the copovidone has a glass transition temperature of 100 ℃ to 110 ℃.
In some embodiments, the copovidone is a regular or coarse powder type copovidone. In some embodiments, the copovidone is composed of 1-ethylAlkenyl-2-pyrrolidone and vinyl acetate are copolymerized in a mass ratio of 3:2, where nitrogen [ N ] is calculated as the anhydride]Content of 7.0% to 8.0% and copolymer vinyl acetate (C) 4 H 6 O 2 ) The content is 35.3 to 41.4 percent. The CAS number for copovidone is 25086-89-9. Copovidone may have different names according to different naming conventions or conventions, such as copovidone, poly (1-vinylpyrrolidone-vinyl acetate), polyvinylpyrrolidone-vinyl acetate copolymer, PVP/VA copolymer, VP/VA copolymer 60/40, etc. The copovidone may also have different trade names according to the names of different companies, such as BASF
Figure BDA0003851854170000071
VA64 or
Figure BDA0003851854170000072
VA64fine (fine powder type), available from Ashland, inc
Figure BDA0003851854170000073
S-630, of Bo ai New open Source (BOAI NKY MEDICAL Holdings)
Figure BDA0003851854170000074
VA64, and Stecke Redenmeier materials technology, inc. (Star-Tech)&JRS Specialty Products) of the related art
Figure BDA0003851854170000075
VA64。
In some embodiments, component (a) of the extrusion mixture: the weight ratio is 1:5-70 (i.e. 1-60, 1-5-1-5-15, 1-5-1-10-1, 1.
In some embodiments, the extrusion mixture further comprises (c) 0.03 to 10 parts of one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of: non-volatile weak acids, neutral and weak acid inorganic substances, and pharmaceutically acceptable adjuvants with melting point lower than 130 deg.C, 120 deg.C, 110 deg.C, 100 deg.C, 90 deg.C or 80 deg.C.
Examples of non-volatile weak acids include, but are not limited to, citric acid anhydrous, citric acid monohydrate, and mixtures thereof. Examples of neutral and weakly acidic inorganics include, but are not limited to, mannitol, lactose monohydrate, lactose anhydrous, sorbitol, dibasic calcium phosphate anhydrous, and colloidal silica.
In some embodiments, the one or more pharmaceutically acceptable excipients include a pharmaceutically acceptable excipient having a melting point of less than 80 ℃. In some embodiments, the pharmaceutically acceptable excipient having a melting point below 80 ℃ is selected from the group consisting of: polyethylene glycols, such as polyethylene glycol 4000 and polyethylene glycol 6000; lipid materials such as triethyl citrate, polyethylene glycol succinate; antioxidants such as 2,6-di-tert-butyl-p-cresol and vitamin E; and surfactants such as poloxamer 188 and tween 8.
In some embodiments, the one or more pharmaceutically acceptable excipients have a melting point of less than 80 ℃ and are selected from the group consisting of: anhydrous citric acid and monohydrate citric acid. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of: mannitol, lactose monohydrate, lactose anhydrous, sorbitol, calcium hydrogen phosphate anhydrous and colloidal silicon dioxide.
In some embodiments, component (a) in the extrusion mixture: (b): (c) In a weight ratio of 1:5-70 (i.e., 1 part by weight of component (a), 5-70 parts by weight of component (b), and 0.03-10 parts by weight of component (c)), 1:5-65, 0.03-10,1: -20-10,1-10-15, the following is from 20 to 10,1 to 10,10.
In some embodiments, component (a) in the extrusion mixture: (b): (c) From 1:5-70: -70-3,1-15-65, 1-25-3,1: -3,1.
In some embodiments, component (a) in the extrusion mixture: (b): (c) The weight ratio is 1:5-70: -70-0.2-2,1-15-65, the following.
In some embodiments, the extrusion mixture comprises the following components in parts by weight:
(a) 1 part of a compound of formula (I);
(b) 15 to 45 parts of copovidone with a glass transition temperature of 100 to 120 ℃; and
(c) 0.1 to 3.0 parts of one or more pharmaceutically acceptable excipients selected from the group consisting of: non-volatile weak acids, neutral and weak acidic inorganic substances, and pharmaceutically acceptable adjuvants with melting point lower than 80 deg.C.
In some embodiments, the copovidone in (b) has a glass transition temperature of from 100 ℃ to 110 ℃. In some embodiments, the pharmaceutical mixture comprises 20 to 40 parts, preferably 20 to 35 parts, more preferably 22 to 33 parts of copovidone.
Extrusion mixture comprising hydroxypropyl methylcellulose
In some embodiments, the extrusion mixture comprises the following components in parts by weight:
(a) 1 part of a compound of formula (I) and (b) 3 to 40 parts of hydroxypropylmethylcellulose having a glass transition temperature of 90 to 130 ℃.
In some embodiments, the compound of formula (I) is in a crystalline form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in an amorphous form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in the form of a hydrate or solvate.
In some embodiments, the hydroxypropyl methylcellulose has a glass transition temperature of 90 ℃ to 120 ℃. In some embodiments, the hydroxypropyl methylcellulose has a glass transition temperature of 100 ℃ to 120 ℃. In some embodiments, the hydroxypropyl methylcellulose has a glass transition temperature of 90 ℃ to 110 ℃. In some embodiments, the hydroxypropyl methylcellulose has a glass transition temperature of from 100 ℃ to 110 ℃.
In some embodiments, the hydroxypropyl methylcellulose has a CAS number of 9004-65-3. In some embodiments, a suitable hydroxypropyl methylcellulose is of dow Chemical (Tao Chemical) having a viscosity of 15cP (HME 15 LV) or 100cP (HME 100 LV)
Figure BDA0003851854170000131
In some embodiments, component (a) in the extrusion mixture: (b) The weight ratio is 1:2-40,1.
In some embodiments, the extrusion mixture further comprises (c) 0.03 to 10 parts of one or more pharmaceutically acceptable excipients.
In some embodiments, the one or more pharmaceutically acceptable excipients in (c) are selected from the group consisting of: non-volatile weak acids, neutral and weak acid inorganic substances, and pharmaceutically acceptable adjuvants with melting point lower than 130 deg.C, 120 deg.C, 110 deg.C, 100 deg.C, 90 deg.C or 80 deg.C. Examples of non-volatile weak acids include, but are not limited to, citric acid anhydrous, citric acid monohydrate, and mixtures thereof. Examples of neutral and weakly acidic inorganics include, but are not limited to, mannitol, lactose monohydrate, lactose anhydrous, sorbitol, dibasic calcium phosphate anhydrous, and colloidal silica.
In some embodiments, the one or more pharmaceutically acceptable excipients have a melting point of less than 80 ℃ and are selected from the group consisting of: polyethylene glycols, such as polyethylene glycol 4000 and polyethylene glycol 6000; lipid materials such as triethyl citrate, polyethylene glycol succinate; antioxidants such as 2,6-di-tert-butyl-p-cresol and vitamin E; and surfactants such as poloxamer 188 and tween 8.
In some embodiments, the one or more pharmaceutically acceptable excipients have a melting point of less than 80 ℃ and are selected from the group consisting of: anhydrous citric acid and monohydrate citric acid. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of: mannitol, lactose monohydrate, lactose anhydrous, sorbitol, calcium hydrogen phosphate anhydrous and colloidal silicon dioxide.
In some embodiments, component (a) in the extrusion mixture: (b): (c) From 1:2-40 to 10, from 2-10, from.
In some embodiments, component (a) in the extrusion mixture: (b): (c) From 1:2-40 to 2-3, from.
In some embodiments, component (a) in the extrusion mixture: (b): (c) 2-30.
In some embodiments, the extrusion mixture comprises the following components in parts by weight:
(a) 1 part of a compound of formula (I);
(b) 6 to 20 parts of hydroxypropyl methylcellulose having a glass transition temperature of 100 to 120 ℃; and
(c) 0.1 to 3.0 parts of one or more pharmaceutically acceptable excipients selected from the group consisting of: non-volatile weak acid, neutral inorganic substance, weak acid inorganic substance, and other pharmaceutically acceptable adjuvants with melting point below 80 deg.C.
In some embodiments, the compound of formula (I) is in a crystalline form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in an amorphous form free of solvent or water of crystallization. In some embodiments, the compound of formula (I) is in the form of a hydrate or solvate. In some embodiments, the extrusion mixture comprises 9 to 15 parts of (b). In some embodiments, the extrusion mixture comprises 0.2 to 2 parts of (c). In some embodiments, the non-volatile weak acid in (c) is selected from the group consisting of: citric acid anhydrous, citric acid monohydrate and mixtures thereof. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of: mannitol, lactose monohydrate, lactose anhydrous, sorbitol, calcium hydrogen phosphate anhydrous and colloidal silicon dioxide. In some embodiments, the other pharmaceutically acceptable excipients having a melting point below 80 ℃ are selected from the group consisting of: polyethylene glycols, such as polyethylene glycol 4000 and/or polyethylene glycol 6000; lipid materials such as triethyl citrate, polyethylene glycol succinate; antioxidants such as 2,6-di-tert-butyl-p-cresol and vitamin E; and surfactants such as poloxamer 188 and tween 8.
Pharmaceutical compositions
Another aspect of the present application relates to a pharmaceutical composition comprising an extrudate of the extruded mixture of the present application and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition can be used to treat steatohepatitis and disorders associated with steatohepatitis.
In some embodiments, the pharmaceutical composition comprises an extrudate made from the extrusion mixture of the present application. In some embodiments, the extrudate is in the form of a granule or powder. In some embodiments, the pharmaceutical application further comprises one or more pharmaceutically acceptable carriers.
Examples of such pharmaceutically acceptable carriers include, but are not limited to, calcium carbonate, calcium phosphate, silica, sugars, starch, cellulose derivatives, gelatin, sodium stearyl fumarate, polymers such as polyethylene glycol, water, saline, phosphate buffered saline, dextrin, glycerol, ethanol, polyols such as mannitol, sorbitol, and sodium chloride.
In some embodiments, the pharmaceutical composition comprises an extrudate and one or more pharmaceutical carriers, the extrudate: the weight ratio of the drug carrier is in the range of 1.1 to 1, 0.1 to 1.
In some embodiments, the pharmaceutical composition further comprises a wetting or emulsifying agent, a preservative, or a buffering agent, which increases the shelf life or effectiveness of the therapeutic agent.
In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as a tablet, capsule, granule, or dry suspension. In some embodiments, the pharmaceutical composition is formulated as a tablet or capsule. In some embodiments, the pharmaceutical composition is formulated as a hydroxypropyl cellulose capsule.
Preparation method
Another aspect of the present application relates to a method for making the extrudate of the present application. The method comprises the following steps: the extrusion mixture of the present application is extruded by hot melt extrusion at an extrusion die or extrusion outlet temperature (hot melt extrusion temperature) of 80 ℃ to 135 ℃ to produce an extrudate. In some embodiments, the hot melt extrusion temperature is between 100 ℃ and 130 ℃. In some embodiments, the hot melt extrusion temperature is between 80 ℃ and 130 ℃, between 80 ℃ and 120 ℃, between 80 ℃ and 110 ℃, between 80 ℃ and 100 ℃, between 80 ℃ and 90 ℃, between 90 ℃ and 130 ℃, between 90 ℃ and 120 ℃, between 90 ℃ and 110 ℃, between 90 ℃ and 100 ℃, between 100 ℃ and 130 ℃, between 100 ℃ and 120 ℃, between 100 ℃ and 110 ℃, between 110 ℃ and 130 ℃, between 110 ℃ and 120 ℃, or between 120 ℃ and 130 ℃.
In some embodiments, the extruding step is performed using a twin screw hot melt extrusion device. In some embodiments, the twin screw hot melt extrusion device has a screw diameter between 8mm and 50mm and an extrusion speed between 10rpm and 300 rpm.
In some embodiments, hot melt extrusion is performed with a residence time (i.e., the time period between the time the extrusion mixture enters the hot melt extrusion device and the time the extrusion mixture is extruded at the die) of less than 30min, 25min, 20min, 15min, or 10 min. In some embodiments, hot melt extrusion is performed with a residence time of 15 min.
In some embodiments, the method further comprises the step of cooling the extrudate. In some embodiments, the method further comprises the step of breaking, crushing, grinding or cutting the extrudate into granules (granules), particles (particles) or powder. In some embodiments, the method further comprises the step of sieving and drying the granules, granules or powder of the extrudate.
In some embodiments, the hot melt extrudate is crushed or cut into granules or powders after cooling. The obtained granule or powder can be directly encapsulated to make into capsule, or can be packaged into granule to make into granule. The resulting granules or powders may also be mixed with other pharmaceutically acceptable carriers and further processed into tablets, capsules, granules or dry suspensions.
Another aspect of the present application relates to a method for preparing the pharmaceutical composition of the present application. The method comprises the following steps:
the extrudates of the present application are processed into tablets or capsules. In some embodiments, the processing step comprises the sub-steps of: the granules, granules or powder of the extrudate are mixed with one or more pharmaceutically acceptable carriers and the resulting mixture is processed into tablets, capsules, granules or a dry blend, preferably tablets or capsules.
In some embodiments, the pharmaceutical compositions of the present application are processed into tablets or filled into capsules. In some embodiments, the pharmaceutical composition of the present application is filled into a hydroxypropyl methylcellulose capsule.
According to a specific embodiment of the present application, the process for the preparation of the pharmaceutical composition of the present application comprises the steps of:
1. active Pharmaceutical Ingredient (API) and adjuvant pretreatment: API and auxiliary materials to be used for formula research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture so as to enable the auxiliary materials to meet the standard of further preparation;
2. preparing materials: weighing API and adjuvants for hot melt extrusion according to prescription proportion and preparation scale;
3. mixing: mixing the formulated API and adjuvant in a manner conventional in formulation technology to form an extruded mixture;
4. hot-melt extrusion: setting the extrusion temperature for different areas of the extruder; after preheating to a set temperature, preserving heat for 15-30 min, uniformly adding the extrusion mixture in a manual feeding or weight-loss automatic feeder feeding mode, and extruding at a preset extrusion speed; controlling the temperature of the extrusion die head between 100 ℃ and 130 ℃ by adjusting the temperature, the screw rotating speed and the feeding speed of different areas of the extruder barrel, keeping the screw torque in a stable range, and enabling the extrudate (extrudate) to be transparent; adjusting the extrusion speed and the feeding speed to control the retention time of the material in a hot melting extruder barrel within 30 min;
5. crushing an extrudate: crushing the cooled extrudate by conventional means of formulation technology;
6. total mixing: adding other carriers/auxiliary materials according to the proportion of the prescription, and mixing the materials by a conventional mixing method to prepare a medicine mixture;
7. preparing a preparation: processing the medicine mixture into tablets or capsules according to the proportion of each prescription;
8. packaging: packaging the tablets or capsules by a suitable method;
9. and (3) storage: the packaged pharmaceutical tablets or capsules containing the compound of formula (I) are stored at room temperature (not more than 30 ℃).
Methods of treatment
Another aspect of the present application relates to a method for treating steatohepatitis or a steatohepatitis-related disorder in a subject. The method comprises the following steps: administering to a subject in need of such treatment an effective amount of a pharmaceutical composition of the present application. In some embodiments, the pharmaceutical compositions of the present application are administered orally. In some embodiments, the pharmaceutical compositions of the present application are administered orally in the form of tablets or capsules. In some embodiments, the pharmaceutical compositions of the present application are administered twice a day, daily, or every other day.
Examples of steatohepatitis-related disorders include, but are not limited to, steatosis, hepatocyte ballooning, fibrosis, and cirrhosis.
After repeated experimental studies, the inventors have unexpectedly found that the pharmaceutical composition of the present application not only can greatly improve the in vitro solubility of the compound of formula (I), but also can meet the requirement of long-term room temperature storage of the heat-unstable compound of formula (I).
The pharmaceutical composition of the present application has the advantages of:
(1) The pharmaceutical composition of the application can greatly improve the dissolution rate of the compound of the formula (I) and achieve the supersaturation maintenance time similar to that of the prior art;
(2) The pharmaceutical compositions of the present application can be stored at room temperature (no more than 30 ℃) for long periods of time without refrigeration.
The present application is further illustrated by the following examples which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application, as well as the figures and tables, are incorporated by reference into this application.
Examples
Example 1
The prescription composition is as follows:
TABLE 1 formulation of example 1
Figure BDA0003851854170000211
Figure BDA0003851854170000221
The preparation process comprises the following steps:
pretreatment of API and auxiliary materials: API and auxiliary materials to be used for prescription research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture so as to enable the auxiliary materials to meet the standard of further preparation;
2. preparing materials: weighing API and auxiliary materials for hot-melt extrusion according to the prescription proportion and the preparation scale;
3. mixing: mixing the API and the auxiliary materials which are prepared by the conventional method of the preparation technology;
4. hot-melt extrusion: setting the extrusion temperature for different areas of the extruder; after preheating to the set temperature, preserving the heat for 15-30 min, uniformly adding the uniformly mixed API and auxiliary materials in a manual feeding or weightless automatic feeder feeding mode, and extruding at a preset extrusion speed; controlling the temperature of an extrusion die head between 100 ℃ and 130 ℃ by adjusting the temperature, the rotating speed and the feeding speed of a screw in different areas of an extruder barrel, keeping the torque of the screw in a stable range, and enabling extruded materials to be transparent; adjusting the extrusion speed and the feeding speed to control the retention time of the material in a hot melting extruder barrel within 30 min;
5. crushing an extrudate: crushing the cooled extrudate by conventional means of formulation technology;
6. total mixing: adding additional auxiliary materials according to the proportion of the prescription, and mixing the materials by a conventional mixing means of a preparation technology;
7. preparing a preparation: the formulations A1, D1 and E1 were compressed into 13 mm. Times.6 mm (length. Times.width) capsule-type tablets, and the hardness of the tablets was controlled to 70N to 130N. The formulation F1 was compressed into 17.2 mm. Times.8.1 mm (length. Times.width) capsule-type tablets, and the hardness of the tablets was controlled to be between 90N and 160N. Filling the total mixture of the prescriptions B1 and C1 into Vcaps Plus type 4 hydroxypropyl cellulose capsules;
8. packaging: filling the tablets of formulas A1, D1, E1 and F1 and the capsules of formulas B1 and C1 into a high-density ethylene bottle, and sealing with an aluminum film;
9. and (3) storage: storing the packed bottled tablet or capsule of the compound of formula (I) at room temperature (not higher than 30 ℃).
Example 2
The prescription composition is as follows:
TABLE 2 formulation of example 2
Figure BDA0003851854170000241
The preparation process comprises the following steps:
pretreatment of API and auxiliary materials: API and auxiliary materials to be used for prescription research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture, so that the auxiliary materials meet the standard of further preparation;
2. preparing materials: weighing API and auxiliary materials for hot-melt extrusion according to the prescription proportion and the preparation scale;
3. mixing: uniformly mixing the API and the auxiliary materials by a conventional method of a preparation technology;
4. hot-melt extrusion: the extrusion temperatures were set for different zones of the extruder. After preheating to the set temperature, preserving heat for 15min-30min, uniformly adding the uniformly mixed API and auxiliary materials in a manual feeding or weight-loss automatic feeder feeding mode, and extruding at a preset extrusion speed. The temperature of the extrusion die head is controlled between 100 ℃ and 130 ℃ by adjusting the temperature, the screw rotating speed and the feeding speed of different areas of the extruder barrel, the screw torque is kept in a stable range, and the extruded material is transparent. Adjusting the extrusion speed and the feeding speed to control the retention time of the material in a hot melting extruder barrel within 30 min;
5. crushing an extrudate: crushing the cooled extrudate by a conventional method of a preparation technology and sieving the crushed extrudate by a 40-mesh sieve;
comparative example 1
Prepared according to the formula a2 in the table 2 and the following preparation process.
TABLE 3 formulation composition of comparative example 1
Composition prescription (mg) a2
Granulation section /
A compound of formula (I) 5
Beta-cyclodextrin 99
Citric acid anhydrous 0.5
Colloidal silicon dioxide 0.5
Total amount of wet granulation 105
Auxiliary materials /
Anhydrous calcium hydrogen phosphate 45
Mannitol 126
Colloidal silicon dioxide 1.5
Sodium stearyl fumarate 2.5
Total amount of auxiliary materials 175
Total amount of 280
The preparation process comprises the following steps:
pretreatment of API and auxiliary materials: API and auxiliary materials to be used for prescription research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture so as to enable the auxiliary materials to meet the standard of further preparation;
2. preparing materials: weighing the API and the auxiliary materials for wet granulation according to the prescription proportion and the preparation scale;
3. mixing: mixing the API and the auxiliary materials which are prepared by the conventional method of the preparation technology;
4. and (3) wet granulation: water is used as a bonding agent, the water is uniformly added into the uniformly mixed granulation API and auxiliary materials, granulation is carried out by passing through a 24-mesh stainless steel screen, and the wet granules after granulation are dried in a forced air oven at 65 ℃ until the moisture content is lower than 3% (rapid moisture determination by an infrared weight loss method at 105 ℃).
5. Straightening: granulating the dried granules by a 24-mesh stainless steel sieve;
6. total mixing: adding other auxiliary materials according to the proportion of the prescription, and mixing the materials by a conventional mixing means of a preparation technology;
7. preparing a preparation: pressing the totally mixed granules into capsule type tablets with the length of 13mm-6mm (length multiplied by width), and controlling the hardness of the tablets to be 70N-130N;
8. and (3) packaging: filling the tablets of the formula a2 into a high-density ethylene bottle and sealing the bottle by using an aluminum film;
9. and (3) storage: the packaged bottled tablets of the compound of formula (I) are stored at room temperature (not more than 30 ℃).
Comparative example 2
The prescription composition is as follows:
TABLE 4 formulation composition of comparative example 2
Figure BDA0003851854170000261
Figure BDA0003851854170000271
The preparation process comprises the following steps:
pretreatment of API and auxiliary materials: API and auxiliary materials to be used for prescription research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture so as to enable the auxiliary materials to meet the standard of further preparation;
2. preparing materials: weighing the API and the auxiliary materials for wet granulation according to the prescription proportion and the preparation scale;
3. mixing: mixing the API and the auxiliary materials which are prepared by the conventional method of the preparation technology;
4. hot-melt extrusion: setting extrusion temperatures for different zones of the extruder; after preheating to a set temperature, preserving heat for 15-30 min, uniformly adding the uniformly mixed API and auxiliary materials in a manual feeding or weight-loss automatic feeder feeding mode, and extruding at a preset extrusion speed; the temperature of the extrusion die head is controlled between 100 ℃ and 130 ℃ by adjusting the temperature, the screw rotating speed and the feeding speed of different areas of the extruder barrel, the screw torque is kept in a stable range, and the extruded material is transparent; adjusting the extrusion speed and the feeding speed to control the retention time of the material in a hot melting extruder barrel within 30 min;
5. crushing an extrudate: crushing the cooled extrudate by conventional means of formulation technology;
6. total mixing: adding other auxiliary materials according to the proportion of the prescription, and mixing the materials by a conventional mixing means of a preparation technology;
7. preparing a preparation: compressing the prescription b2 into capsule type tablet with length of 13mm-6mm (length × width), and controlling the hardness of the tablet at 70N-130N; filling the total mixture of the prescription c2 into Vcaps Plus type 4 hydroxypropyl cellulose capsules;
8. packaging: filling the tablets of the formula b2 and the capsules of the formula c2 into a high-density ethylene bottle, and sealing the bottle by using an aluminum film;
9. and (3) storage: the packaged bottled tablets or capsules of the compound of formula (I) are stored at room temperature (not more than 30 ℃).
Comparative example 3
Prepared according to the E1 formula (shown in Table 5 below) in example 1 of the Chinese patent application 202010105909.9 and the following preparation process.
TABLE 5 formulation composition of comparative example 3
Figure BDA0003851854170000281
Figure BDA0003851854170000291
The preparation process comprises the following steps:
1. preparing a blank matrix: sequentially adding polyethylene glycol 1000, polyethylene glycol 4000, polyethylene glycol 6000, poloxamer 188 and anhydrous citric acid at 65 deg.C, and stirring to completely melt;
2. removing bubbles: standing to eliminate bubbles completely;
3. adding a compound of formula (I): adding the raw material medicine of the compound shown in the formula (I) under the stirring state, and continuously stirring to completely melt the raw material medicine in the matrix;
4. filling a capsule: transferring the prepared molten content into a preheated insulating charging barrel of a capsule filling machine, starting a stirring function, filling the molten content into a gelatin hard capsule according to preset filling parameters (the average filling quantity difference is controlled to be less than or equal to 2.5%, and the single-particle capsule filling quantity difference is controlled to be less than or equal to 5.0%), and covering a capsule cap;
5. and (3) cooling: spreading the mixture in a room temperature environment to rapidly cool and solidify the contents;
6. packaging: putting the capsule into a high-density ethylene bottle and sealing the bottle by using an aluminum film;
7. and (3) storage: the bottled compound capsule of the formula (I) is stored at 2-8 ℃.
Comparative example 4
Prepared according to the e2 and f2 recipes in table 6 and the following preparation process.
TABLE 6 formulation composition of comparative example 4
Figure BDA0003851854170000301
The preparation process comprises the following steps:
1, API and auxiliary material pretreatment: API and auxiliary materials to be used for prescription research are crushed, sieved and dried by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture, so that the auxiliary materials meet the standard of further preparation;
2. preparing materials: weighing API and auxiliary materials for hot-melt extrusion according to the prescription proportion and the preparation scale;
3. mixing: uniformly mixing the API and the auxiliary materials by a conventional method of a preparation technology;
4. hot-melt extrusion: setting extrusion temperatures for different zones of the extruder; after preheating to the set temperature, preserving heat for 15min-30min, uniformly adding the uniformly mixed API and auxiliary materials in a manual feeding or weightless automatic feeder feeding mode, and extruding at a preset extrusion speed; the temperature of the extrusion die head is controlled between 100 ℃ and 130 ℃ by adjusting the temperature, the screw rotating speed and the feeding speed of different areas of the extruder barrel, the screw torque is kept in a stable range, and the extruded material is transparent; adjusting the extrusion speed and the feeding speed to control the retention time of the material in a hot melting extruder barrel within 30 min;
5. crushing an extrudate: crushing the cooled extrudate by a conventional method of a preparation technology and sieving the crushed extrudate by a 40-mesh sieve;
comparative example 5
Prepared according to the formula of g2 in table 7 and the following preparation process.
TABLE 7 formulation composition of comparative example 4
Composition prescription (mg) g2
A compound represented by the formula (I) 5
Copovidone Kollidon VA64 165
Mannitol 150
Total amount of 320
The preparation process comprises the following steps:
1, API and auxiliary material pretreatment: crushing, sieving and drying API and auxiliary materials to be used for prescription research by a conventional means of a preparation technology to remove caking in the storage process and reduce the moisture content of the auxiliary materials which are easy to absorb moisture so as to enable the auxiliary materials to meet the standard of further preparation;
2. preparing materials: weighing API and adjuvants for dry granulation according to prescription proportion and preparation scale;
3. mixing: mixing API and adjuvants with the final product ingredients (finished ingredients) by conventional method of preparation technology;
4. and (3) dry granulation: the well mixed API and excipient were rolled under a pressure of 5.0MPa and flaked.
5. Grading: sieving and grading by using a 24-mesh stainless steel sieve;
6. packaging: packaging the particles obtained by the formula e2 into double aluminum strips according to the dosage, and sealing;
7. and (3) storage: packaged tablets of a compound of formula (I) are stored at room temperature (not more than 30 ℃).
Effect example 1
The granules obtained by hot-melt extrusion and then grinding according to recipes A1 to F1 of example 1 were weighed, the granules obtained by wet granulation and drying according to recipe a2 of comparative example 1 were ground, the granules obtained by hot-melt extrusion and then grinding according to recipes b2 and c2 of comparative example 2 were ground, and capsules according to recipe d2 of comparative example 3 were prepared, and 6 samples were subjected to comparative study of dissolution profile in water.
Dissolution conditions: the dissolution medium was 37 ℃. + -. 0.5 ℃ and 900mL of degassed water, and the paddle speed was 50rpm. The granules were directly weighed accurately and placed in a drop-out basket and the capsules prepared according to d2 prescription of comparative example 3 were placed in a drop-out basket. Samples were taken at 10, 20, 30, 45, 60, 90 and 120min, respectively. The filtrate was then diluted with an equal proportion of 75% acetonitrile in water. The concentration of the compound represented by the formula (I) was determined by HPLC. The cumulative percent dissolution of the compound of formula (I) was calculated at different time points.
HPLC determination conditions: chromatographic column with octadecylsilane chemically bonded silica as filler (Welch)
Figure BDA0003851854170000321
XB-C18.4.6 x 150mm,5 μm, or equivalent column), and purified with 0.05% aqueous trifluoroacetic acid-acetonitrile (30: 70 ) is a mobile phase, the flow rate is 1.0ml/min, the column temperature is 30 ℃, and the detection wavelength is 230nm. The control solution and the sample solution were precisely injected into the column in an amount of 20. Mu.l each (50. Mu.l for the B1 and C1 prescriptions of 1mg standard and 10. Mu.l for the F1 prescriptions of 10mg standard), the chromatogram was recorded, and the elution amount of each capsule was calculated as the peak area according to the external standard method.
As a result:
I. as shown in table 8 and fig. 1, the compound of formula (I) achieved the highest dissolution >85% results similar to the results of the semi-solid capsule of chinese patent application 202010105909.9 (compared to the results of the d2 prescription of comparative example 3 in table 9 and fig. 2) with the ratio of the embodiments of the present invention.
Beta-cyclodextrin is a common solubilizing auxiliary material, and after a poorly soluble drug is subjected to wet granulation with the poorly soluble drug, the dissolution of the poorly soluble drug can be improved to a certain extent. However, the experimental results using the a2 formulation of example 1 show that the compound of formula (I) has a dissolution rate of less than 1% at a higher proportion (1. This indicates that the dissolution of the compound of formula (I) may not be enhanced by the optional use of conventional solubilization means.
In the formulation of b2 of comparative example 2, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus, which is a common hot-melt extrusion adjuvant for solubilization, was mixed with a compound represented by formula (I) in a ratio of 22. This indicates that the optional use of a hot melt extrusion adjuvant for solubilization does not necessarily have a solubilizing effect on the compound of formula (I).
In the b2 formulation of comparative example 2 copovidone Kollidon VA64 is hot melt extruded with the compound of formula (I) in the ratio 1. It can be seen that the proportions of different adjuvants required to achieve solubilization vary.
And (4) conclusion:
simple solubilization means, such as solubilization with beta-cyclodextrin, are not suitable for increasing the dissolution of the compound of formula (I); simple application of hot melt extrusion techniques without screening materials, such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus, is not suitable for increasing the dissolution of the compound of formula (I); the solubilization effect is not ideal simply by selecting a high proportion of adjuvants, such as copovidone Kollidon VA64 in a ratio of 1. Therefore, the compound shown in the formula (I) can be satisfactorily solubilized only by selecting specific solubilizing materials and keeping the reasonable proportion.
Table 8 dissolution results in water (n = 6) for different prescription samples in example 1
Figure BDA0003851854170000341
TABLE 9 dissolution in water results (n = 6) for different prescription samples in the comparative examples
Figure BDA0003851854170000342
Effect example 2
The pH of the digestive juices of the human gastrointestinal tract are increasing. Maintaining high supersaturation after oral administration is a prerequisite for poorly soluble drugs to be absorbed into systemic circulation to exert their pharmacological effects. In this example, a simple in vitro dissolution test design (dissolution test of 2h + 4h) was used to illustrate the reasons for selecting the composition ratios and preparation processes of the present invention.
The granules obtained by hot-melt extrusion according to the recipe G1-L1 of example 2, the granules obtained by hot-melt extrusion according to the recipe G2-f2 of comparative example 4, and the granules obtained by dry granulation according to the recipe G2 of comparative example 5 were weighed, and the pH transition and supersaturation maintenance time of the simulated human digestive fluid were examined.
The dissolution conditions were as follows: first, 750mL of a degassed hydrochloric acid solution at 37 ℃. + -. 0.5 ℃ at pH 2.0 was used as a dissolution medium and dissolution was performed by stirring at 50rpm for 2 hours by the paddle method, and then, 250mL of a degassed 200mM phosphate buffer solution at pH 6.8 was added and dissolution was continued by stirring at 50rpm for 4 hours by the paddle method. The particles were weighed accurately directly and placed, and samples were taken 15, 30, 45, 60, 90, 120, 180, 210, 240 and 360min after placement, and the subsequent filtrates were diluted with 75% acetonitrile in water in equal proportions and the concentration of the compound of formula (I) was determined by HPLC and calculated at different time points
The HPLC measurement conditions were the same as those in Effect example 1.
As a result:
I. as shown in table 10 and fig. 3, the compounds of formula (I) achieved the highest dissolution of >60% and maintained the dissolution of >30% at 6 h.
When the copovidone ratio is reduced below 15 parts, as in e2 and f2 of comparative example 4, the highest dissolution was only 46.1% and 7.1% when the copovidone ratio was reduced to 12.54 parts and 8.25 parts, respectively, and the dissolution at 6h was only 19.4% and 4.4%. This indicates that the formulation of copovidone is directly related to the solubilization effect and that it is difficult to maintain a high degree of supersaturation concentration when the amount is less than 15 parts.
In the g2 formulation of comparative example 5, the amount of copovidone was 33 parts, but since the dry granulation process was used instead of hot melt extrusion, the result showed less than 1% dissolution in 6 hours. This indicates that the solubilizing effect of the compound of formula (I) is achieved only after hot melt extrusion and that the manufacturing process is very important for the performance of the composition.
And (4) conclusion:
the results of example 2 again show that higher dissolution rates and longer supersaturation maintenance times can only be achieved with specific ratios of copovidone and specific hot melt extrusion manufacturing processes.
Table 10 effect dissolution results of the preparation sample of example 2 (n = 6)
Figure BDA0003851854170000361
Figure BDA0003851854170000371
TABLE 11 dissolution results of the prescription samples in comparative examples 4-5 (n = 6)
Figure BDA0003851854170000372
Effect example 3
Capsules prepared according to the prescription B1 of example 1 and tablets prepared according to the prescription E1 were weighed, placed in high density polyethylene bottles, respectively, sealed with aluminum film, and then subjected to an accelerated test at a temperature of 30 ℃ ± 2 ℃ and a relative humidity of 65% ± 5%. Capsules prepared according to the formulation d2 of comparative example 3 were weighed, placed in a high density polyethylene bottle, sealed with an aluminum film, and then subjected to an accelerated test at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60%. + -. 10%. At the accelerated 1 month time point, the assay for the relevant substances was performed on group B1 capsules, group E1 tablets and group d2 capsules.
Related substance assay: using a chromatographic column (ACE ultracore2.5 super c18 (4.6 × 150mm) or equivalent in potency) with octadecylsilane bonded silica as a packing material, and eluting with a gradient (volume ratio) according to table 12 using 10mM potassium dihydrogen phosphate aqueous solution as mobile phase a and acetonitrile as mobile phase B; flow rate: 1.0mL/min, detection wavelength: 278nm, column temperature: at 45 ℃.
Table 12.
Time (min) Mobile phase A (%) Mobile phase B (%)
0.00 80 20
0.50 80 20
8.00 45 55
15.00 45 55
25.00 30 70
50.00 15 85
50.10 80 20
55.00 80 20
Weighing a proper amount of the compound shown in the formula (I) and an impurity reference substance, adding acetonitrile to dissolve and dilute the compound and the impurity reference substance to prepare solutions containing 0.5mg of the compound shown in the formula (I) and 0.001mg of the impurity in each 1ml of the solution, and using the solutions as system adaptability test solutions. 50 μ l was precision injected into a liquid chromatograph and the chromatogram recorded. It is known that the degree of separation between the impurity and the adjacent peak should not be less than 1.5. Taking 10 capsules of the product, accurately weighing, pouring the content into a 100ml volumetric flask, washing the inner wall of the capsules by acetonitrile in a graded manner, adding the washing liquid into the volumetric flask (for tablets, taking 10 tablets of the product, accurately weighing, grinding into fine powder, accurately weighing a proper amount of tablet powder), adding acetonitrile to dissolve, and preparing a solution containing 0.5mg of the compound shown in the formula (I) in each 1ml of the solution as a test solution; precisely measuring 50 μ l of the test solution, injecting into a liquid chromatograph, and recording chromatogram. The total amount of impurities and all impurities in the compound capsule (or tablet) of formula (I) was calculated according to peak area normalization.
As a result:
I. as shown in Table 13, for example 1, capsules and tablets prepared according to the formulations B1 and E1 were examined at 30 ℃. + -. 2 ℃ and 65%. + -. 5% relative humidity for 1 month at an accelerated speed, and the results of the substance measurement revealed that no significant change was observed in all of the known simple impurities, unknown simple impurities and total impurities (total impurities) of the compound represented by the formula (I), and particularly, the sum of GLC02-Z6 and GLC02-Z7 was increased by only 0.02% and 0.04%, respectively. For the production batches, as shown in table 14, for example 1, the capsules and tablets prepared according to formulas B1 and E1 were examined at 30 ℃ ± 2 ℃ and 65% ± 5% relative humidity for 6 months at an accelerated speed, and the relevant material determination results revealed that no significant change was observed in all of the known monoimpurities, unknown monoimpurities and total impurities of the compound of formula (I).
As shown in table 13, for comparative example 3, after accelerated examination of the capsules prepared according to the d2 formulation at a temperature of 25 ℃ ± 2 ℃ and a relative humidity of 60% ± 10% for 1 month, the related substances were determined to increase the sum of GLC02-Z6 and GLC02-Z7 by 1.32%, the total impurities by 1.14%, and the related substances were significantly changed. For the production batches, as shown in table 14, for comparative example 3, after accelerated stability examination for 3 months under conditions of 25 ℃ ± 2 ℃ and 60% ± 10% relative humidity for capsules prepared according to the d2 formulation, the measurement results of the related substances found that GLC02-Z6 increased by 2.69% after GLC02-Z7, the total impurities increased by 2.0%, and the related substances were significantly changed.
TABLE 13 Effect of accelerated stability conditions on related substances in pharmaceutical products
Figure BDA0003851854170000391
Figure BDA0003851854170000401
TABLE 14 different accelerated stability Studies on the influence of the substances involved in the production batch recipe
Figure BDA0003851854170000411
And (4) conclusion:
the accelerated results show that the capsules or tablets of the compound of formula (I) prepared according to the formulation of example 1 have better results after 6 months of accelerated stability at a temperature of 30 ℃ ± 2 ℃ and a relative humidity of 65% ± 5%, indicating that they have the prospect of long-term storage at room temperature.
Preliminary accelerated stability studies at 25 ℃. + -. 2 ℃ and 60%. + -. 10% relative humidity for 3 months showed that semisolid capsules of the compound of formula (I) prepared according to the formulation of comparative example 3 showed significant changes in the substances involved, in particular in the sum of GLC02-Z6 and GLC02-Z7, indicating that the formulation is suitable only for long-term use at 2 ℃ to 8 ℃ and does not have the possibility of long-term storage at room temperature.
While various embodiments have been described above, it should be understood that these disclosures are presented by way of example only, and not limitation. Thus, the breadth and scope of the subject compositions and methods should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
The above description is intended to teach those of ordinary skill in the art how to practice the invention and does not detail all those obvious modifications and variations that will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention which is defined by the following claims. The claims are intended to cover the components and steps in any sequence which is effective to meet their intended objectives unless the context clearly indicates the contrary.

Claims (20)

1.A pharmaceutical composition comprising the following components in parts by weight:
(a) 1 part of a compound of formula (I);
Figure FDA0003851854160000011
and
(b) 15 to 45 parts of copovidone with a glass transition temperature of 90 to 130 ℃;
wherein components (a) and (b) are mixed and subjected to hot melt extrusion.
2. The pharmaceutical composition of claim 1, wherein components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 80-135 ℃.
3. The pharmaceutical composition according to claim 1, comprising 20 to 40 parts of copovidone.
4. The pharmaceutical composition according to claim 1, comprising 22 to 33 parts copovidone.
5. The pharmaceutical composition of claim 1, further comprising:
(c) 0.1 to 3.0 parts of one or more pharmaceutically acceptable excipients selected from the group consisting of: a non-volatile weak acid, a neutral or weak acid mineral, and a pharmaceutically acceptable excipient having a melting point below 80 ℃, wherein components (a), (b) and (c) are mixed and subjected to hot melt extrusion at a temperature in the range of 80 ℃ to 135 ℃.
6. The pharmaceutical composition of claim 5, wherein the one or more pharmaceutically acceptable excipients comprises citric acid anhydrous, citric acid monohydrate, or a mixture thereof.
7. The pharmaceutical composition of claim 5, wherein the one or more pharmaceutically acceptable excipients comprise one or more neutral or weakly acidic minerals selected from the group consisting of: mannitol, lactose monohydrate, lactose anhydrous, sorbitol, calcium hydrogen phosphate anhydrous and colloidal silicon dioxide.
8. The pharmaceutical composition of claim 5, wherein the one or more pharmaceutically acceptable excipients comprise one or more excipients selected from one or more of group c of: polyethylene glycol, polyethylene glycol 4000, polyethylene glycol 6000; lipid material, triethyl citrate, vitamin E, polyethylene glycol succinate; antioxidant 2,6-di-tert-butyl-p-cresol, surfactant poloxamer 188 and tween 80.
9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated in the form of a tablet or capsule.
10. A process for preparing the pharmaceutical composition of claim 1, comprising the steps of:
extruding a mixture of components (a) and (b) by hot melt extrusion at a hot melt extrusion temperature between 80 ℃ and 135 ℃ to form an extrudate;
cooling the extrudate; and
the cooled extrudate is broken up into granules, granules or powder by cutting, crushing or grinding.
11. The method of claim 10, further comprising the step of:
processing the granules, granules or powder obtained in the crushing step into tablets, capsules.
12. The method of claim 10, wherein the mixture of components (a) and (b) is extruded using a twin screw hot melt extrusion device; wherein the twin screw hot melt extrusion has a screw diameter of between 8mm and 50mm and an extrusion speed of between 10rpm and 300rpm, wherein the residence time of the hot melt extrusion is less than 30min.
13. A method of treating steatohepatitis, comprising the steps of:
administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 1.
14. A pharmaceutical composition comprising the following components in parts by weight:
(a) 1 part of a compound represented by the formula (I);
Figure FDA0003851854160000021
and
(b) 6 to 20 parts of hydroxypropylmethylcellulose having a glass transition temperature of 90 to 130 ℃;
wherein components (a) and (b) are mixed and subjected to hot melt extrusion.
15. The pharmaceutical composition of claim 14, wherein components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 80-135 ℃.
16. The pharmaceutical composition of claim 14, further comprising:
(c) 0.1 to 3.0 parts of one or more pharmaceutically acceptable excipients selected from the group consisting of: a non-volatile weak acid, a neutral or weak acid mineral, and a pharmaceutically acceptable excipient having a melting point below 80 ℃, wherein components (a), (b) and (c) are mixed and subjected to hot melt extrusion at a temperature in the range of 80 ℃ to 135 ℃.
17. The pharmaceutical composition of claim 16, comprising 0.2 to 2.0 parts of one or more pharmaceutically acceptable excipients.
18. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is formulated in the form of a tablet or capsule.
19. A process for preparing the pharmaceutical composition of claim 14, comprising the steps of:
extruding a mixture of components (a) and (b) by hot melt extrusion at a hot melt extrusion temperature between 80 ℃ and 135 ℃ to form an extrudate;
cooling the extrudate; and
the cooled extrudate is broken up into granules, granules or powder by cutting, crushing or grinding.
20. A method of treating steatohepatitis, comprising the steps of:
administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 14.
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